Mechanisms that restrict the immune response are critical to avoid damaging reactivity that can lead to allergies and inflammatory responses or, in more severe cases, to lethal autoimmune diseases. Our goal is to understand mechanisms that downregulate the immune response, control lymphocyte proliferation and antibody production. With this intention we initiated a study of the negative regulatory pathway mediated by the Fc receptor FcgammaRIIB (RIIB) and identified the associating molecule SHIP. Engagement of RIIB by immune complexes results in the abolition of activation signals through the recruitment of the inositol phosphatase SHIP to the membrane. Absence of SHIP results in reduced viability of the mice due to a myeloproliferative-like syndrome, with profound splenomegaly and massive myeloid cell accumulation in the lungs. The very pleiotropic phenotype of SHIP-/- mice reflects the fact that SHIP not only mediates the RIIB inhibitory signal, but is also a general down-modulator of growth factor, interleukin, Fc and antigen receptor activity. To get a more precise idea of the in vivo function of SHIP in specific cells while avoiding pleiotropic interactions, we have begun to characterize tissue-specific or inducible SHIP mutations in mice. We have generated loxP-flanked SHIP mice that can be crossed to several Cre recombinase-expressing mice. There is a manuscript in preparation that describes the essential role of SHIP in the formation of the splenic marginal zone. Macrophage specific SHIP mutants were used for the reported experiments.